Post-traumatic stress disorder (PTSD) seriously disrupts the lives of many Veterans. Current first-line treatments, serotonin reuptake inhibitors or prolonged exposure therapy, take weeks to months to bring meaningful improvement, leaving Veterans experiencing prolonged suffering. A promising new treatment approach for rapidly reducing PTSD symptoms is nitrous oxide, an inhalation anesthetic and putative N-methyl-D-aspartate receptor (NMDAR) modulator that diminishes depression symptoms within 1 day and has limited side effects. If shown to be similarly effective in PTSD, nitrous oxide may add dramatically to our treatment armamentarium by bringing rapid symptom decrease before longer-term therapies take hold. The proposed projects test the efficacy of nitrous oxide in relieving Veteran?s PTSD symptoms and, in parallel, explore how nitrous oxide may modify cognitive and pain outcomes. Nitrous oxide is FDA-approved for use in anesthesia and pain management, and may be a new approach for managing PTSD. Nitrous oxide?s favorable pharmacokinetics (rapid offset in minutes) prevent the transient cognitive and psychotomimetic side effects (delusions, hallucinations) sometimes seen with other NMDA glutamate modulators. Nitrous oxide may be suited to Veterans in view of: 1) their older age (which brings greater probability of age-associated cognitive impairments), and 2) higher prevalence of co-morbid pain than in the US population. As an anesthetic, nitrous oxide has robust evidence regarding its application in pain, and a superior safety record as an analgesic for dental procedures and childbirth. The proposed projects will examine the efficacy of nitrous oxide in relieving Veteran?s PTSD symptoms and in parallel, explore whether nitrous oxide improves cognitive and pain outcomes. Specifically, we will first assess whether nitrous oxide treatment improves PTSD symptoms within 1 week. In parallel, we will explore whether the treatment improves co-existing depression and pain. In addition, we will explore nitrous oxide?s effects on a PTSD-associated impairment that is often overlooked - disruption in cognitive control, a core neurobiological process critical for regulating thoughts and for successful daily functioning. We will test whether the magnitude of nitrous oxide?s effect on PTSD symptoms or pain depends on the Veteran?s baseline capacity for cognitive control or on changes induced in cognitive control. If diminished PTSD symptoms are related to changes in cognitive control, these findings would signal that cognitive control may merit examination in a larger study of mechanism of action. Taken together, if nitrous oxide is found to rapidly relieve Veterans? PTSD symptoms and modify cognitive and pain outcomes, and these results are replicated in a larger study, it could transform psychiatric treatment of PTSD.